The goal of this research is to understand the processes involved in excitotoxic degeneration of synapses using an animal model. Animal models for human neurodegenerative disease are of great value for exploring the cellular and biochemical mediators and molecular pathogenesis of a slowly progressive disease process. The slow channel congenital myasthenic syndrome (SCCMS) is caused by mutations that result in delayed closure of the ion channel of the acetylcholine receptor (AM) of the neuromuscular (NMJ). The delayed channel closure is associated with calcium overload and degeneration of the NMJ, AChR loss, and progressive muscle weakness. Thus, the SCCMS is a prototype for a hereditary excitotoxic disorder. Using transgenic mice technology and site-directed mutagenesis of AChR subunit coding sequences, we have developed the slow-channel transgenic mouse, an animal model for the SCCS that manifest all the features seen in the human disease. In this proposal, the investigator proposes to: (1) Determine whether slow-channel transgenic mice have reduced expression of neuromuscular synapse-specific genes. This will be accomplished by comparison of mRNA levels for the AChR subunit genes and other NMJ-specific genes between transgenic and control mice and between degenerating NMJ nuclei and remote from the NMJ nuclei; (2) Determine the cause(s) of the organellar damage and endplate myopathy in slow-channel mice. Three likely pathways of intracellular damage: activation of calcium-activated proteases, oxidative damage by free radicals, and apoptosis will be explored using a combination of specific antibody probes and stains to look for damaged proteins and DNA at the NMJ and genetic and pharmacological manipulation of these pathways to alter the course of the disease; and (3). Determine if quinidine can protect the slow-channel transgenic mice from endplate degeneration.